Clinical Trial Result Information
Title of Study:
An open-label, multicenter, randomized study to determine dose conversion factors at different frequencies of administration after switching from maintenance treatment with subcutaneous epoetin alfa or beta to maintenance treatment with subcutaneous Mircera in dialysis patients with chronic renal anemia.
Fast Facts:
| Protocol number: | BA16286 |
| Sponsor: | Hoffmann-La Roche Ltd |
| Company division: | Pharmaceutical |
| Product name: | Mircera |
| Generic name: | methoxy polyethylene glycol-epoetin beta |
| Phase of development: | II |
| Therapeutic area, approved indication: | Anemia |
| Date of report: | 3/1/2006 |
Clinical study summary:
This was an open-label, multicenter, randomized trial comparing 3 dose conversion factors and 3 frequencies of administration of subcutaneous (sc) Mircera (methoxy polyethylene glycol-epoetin beta) as maintenance treatment for chronic renal anemia in dialysis patients.
Study center(s) :
22 centers in Germany, Italy, Spain and USA.
Objectives:
The primary objective was to determine the optimal dose conversion factor(s) from epoetin alfa or beta to Mircera and frequencies of Mircera administration which are most likely to provide a stable hemoglobin (Hb) course after switching from a sc maintenance dose of epoetin alfa or beta to a sc maintenance dose of Mircera in patients with chronic kidney disease (CKD) on dialysis. Secondary objectives were to assess and to document the long-term safety and tolerability of SC administration of Mircera in the defined patient population. The objective of the extension period was to document the long-term safety and efficacy of sc Mircera administration in the defined patient population.
Methodology:
Following a 2-week run-in period (to assess Hb level and iron status) patients who previously received epoetin alfa or beta thrice weekly were randomized to receive Mircera 1x/week or 1x/3 weeks, and patients who previously received epoetin alfa or beta once or twice weekly were randomized to receive Mircera 1x/week, 1x/3 weeks, or 1x/4 weeks. Randomization of the patients to the treatment cohorts was performed in a sequential manner. The first patients were randomized to receive a dose of Mircera calculated using a conversion factor of 0.8/150 (=100% of the assumed equi-effective dose of epoetin alfa or beta). When the first 24 patients (eight patients within each cohort) had completed the first 6 weeks of treatment, a Data and Safety Monitoring Board reviewed the patients' safety and efficacy data and confirmed the conversion factors of 0.4/150 and 1.2/150 for the other 6 cohorts. Patients assigned to the 1x/week or 1x/3 weeks dosing schedules were treated for 19 weeks, and patients assigned to the 1x/4 weeks dosing schedule were treated for 21 weeks. Hb and hematocrit (Hct) were assessed weekly. In addition, blood samples were collected for determination of iron parameters, and safety laboratory assessments, and anti-erythropoietin antibodies. Adverse events (AEs) and vital signs were also monitored.
Patients who completed the core treatment period were eligible to enter an optional extended treatment period of up to 54 weeks. During this period, patients continued to receive Mircera at the same frequency of administration as during the core period. Dose adjustments were performed to maintain target Hb levels within 11-12g/dL.
Patients who completed the 54-week extension period were eligible to enter a second optional extended treatment period of up to 54 weeks. During this period, patients continued to receive Mircera at the same frequency of administration as during the first-year extension period. Dose adjustments were performed to maintain target Hb levels within 11-12g/dL.
Number of patients (planned/analyzed):
137 patients enrolled in 9 cohorts (core treatment period); 62 patients entered extension year 1; 42 patients entered extension year 2.
Diagnosis and main criteria for inclusion:
Adult patients (≥18 years old) with CKD on dialysis therapy who had been receiving maintenance treatment with sc epoetin alfa or beta. The dialysis requirements were Kt/V ≥1.2 or urea reduction ratio (URR) ≥65% in hemodialysis and weekly Kt/V ≥1.8 in peritoneal dialysis.
Test product, dose and mode of administration or test procedure:
During the core period, the weekly dose of Mircera was determined by multiplying the patient's previous weekly dose received during the run-in period by one of three conversion factors: low = 0.4/150, medium = 0.8/150, or high = 1.2/150. Mircera was administered sc 1x/week, 1x/3 weeks or 1x/4 weeks.
During the extension years 1 and 2, Mircera was administered by sc either 1x/week, 1x/3 weeks or 1x/4 weeks, after completion of the first hemodialysis session of the week and always on the same day of the week for peritoneal dialysis patients. The initial dose was the final dose from the previous period, which could be adjusted to maintain target Hb levels.
Duration of treatment:
19 or 21 weeks (core treatment period).
Reference therapy, dose and mode of administration or reference procedure:
N/A.
Criteria for evaluation (efficacy, safety):
Efficacy: Primary parameter: Change in Hb from baseline over time.
Secondary parameter: Change in Hct from baseline over time.
Safety: Adverse events (AEs), vital signs, ECG, laboratory safety tests, including hematology, blood chemistry, iron parameters, electrolytes, and anti-Mircera antibodies.
Statistical methods:
Efficacy: The primary endpoint was analyzed by calculating a separate linear regression over time for each patient with all Hb levels until end of intial treatment (EOIT) as the dependent variable. EOIT was defined as the last observed value before a dose change or blood transfusion. The individual slopes were multiplied by 42 to give an estimate of the change in Hb over 6 weeks for each patient and corresponding initial conversion factor (low, medium, high). For each dosing schedule, a regression of these estimates on the three conversion factors was calculated. The value where the regression line crosses zero gives the estimation of the equi-effective conversion factor. The robustness of these results was checked using a time-adjusted mean approach. Similar analyses were performed for the secondary efficacy parameter of change in Hct levels. Efficacy parameters were summarized descriptively during the extension periods.
Safety: AEs, vital signs and laboratory data were summarized descriptively.
Summary (efficacy, safety, other results):
Efficacy: In the intent-to-treat population, the 0.8/150 conversion factor resulted in the most stable Hb levels in comparison with the other conversion factors (median Hb changes over 6 weeks based on slope values for all three dosing schedules of -0.11 g/dL compared with -0.62 g/dL for the 0.4/150 dose group and 0.31 g/dL for the 1.2/150 dose group). Dosing schedule did not appear to have an effect on the stability of Hb levels. This led to similar estimates for the equi-effective conversion factors of the three different dosing schedules with an overall estimate of 0.81 (90% CI 0.74-0.87), which confirmed the initial assumption of 0.8/150. Similar results were obtained using a time-adjusted mean analysis, analysis of Hct, and per-protocol analyses.
The target Hb concentration during the extension period was between 11 and 12 g/dL. During the first extension period, the median Hb concentration ranged from 10.80-11.65 g/dL in the 1x/week dosing group, 10.75-11.80 g/dL in the 1x/3 week dosing group and 10.90-11.60 g/dL in the 1x/4 weeks dosing group. During the second extension period, the median Hb concentration ranged from 10.93-12.15 g/dL in the 1x/week dosing group, 10.84-11.98 g/dL in the 1x/3 weeks dosing group and 10.80-12.10 in the 1x/4 weeks dosing group.
Safety: Long-term administration of Mircera was generally well tolerated. The majority (85%) of patients experienced AEs during the complete study period (core treatment period plus extension periods) and the most commonly reported AEs were infections and infestations. Only four patients had events that were considered to be related to the study medication (hypertension, injection site reaction, aortic valve stenosis and hypoglycemia); none of these related events was a serious AE. There were no drug-related SAEs. Twenty-one patients died during the study (4 during the core study period), but no deaths were considered to be related to the study medication. No trends of significance were found in the laboratory parameters measured in this study. The most common marked laboratory abnormalities were elevated phosphate and potassium concentrations.
In general, the safety profiles for extension year 1, extension year 2 and the complete study period were similar. In addition, the safety profiles between the dosing schedule groups were comparable.
Conclusions:
Overall, maintenance treatment with sc Mircera results in stable Hb levels after switching from maintenance treatment with sc epoetin alfa or beta in patients with chronic kidney disease on dialysis. The dosing schedules tested in this study had no effect on the stability of Hb levels. Long-term administration of sc Mircera resulted in relatively stable Hb levels at all frequencies of administration. Mircera was generally well tolerated long-term, with no marked differences between dose groups in terms of safety.
Publications (references, if available):
Curr Med Res Opin 23:969-979,2007.
Click here for the protocol registry listing of this trial.
